NM_001199138.2:c.2357G>T

Variant names:

• chr2-32238296-C-A
• rs149451729
• NM_001199138.2:c.2357G>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001199138.2(NLRC4):​c.2357G>T​(p.Gly786Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00378 in 1,608,440 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0024 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0039 (16 hom.)
• Consequence: NLRC4 NM_001199138.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:6
• Conservation: PhyloP100: 1.04
• Publications: 13 publications found

Genes affected

NLRC4 (HGNC:16412): (NLR family CARD domain containing 4) This gene encodes a member of the caspase recruitment domain-containing NLR family. Family members play essential roles in innate immune response to a wide range of pathogenic organisms, tissue damage and other cellular stresses. Mutations in this gene result in autoinflammation with infantile enterocolitis. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2014]

NLRC4 Gene-Disease associations (from GenCC):

• periodic fever-infantile enterocolitis-autoinflammatory syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Illumina, Orphanet, Labcorp Genetics (formerly Invitae)
• familial cold autoinflammatory syndrome 4

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ENSG00000289727 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.021336168).
• BP6: Variant 2-32238296-C-A is Benign according to our data. Variant chr2-32238296-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 475252.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0024 (366/152212) while in subpopulation NFE AF = 0.00423 (288/68032). AF 95% confidence interval is 0.00383. There are 4 homozygotes in GnomAd4. There are 156 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 366 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001199138.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NLRC4	NM_001199138.2	MANE Select	c.2357G>T	p.Gly786Val	missense	Exon 6 of 9	NP_001186067.1	Q9NPP4-1
	NLRC4	NM_001199139.1		c.2357G>T	p.Gly786Val	missense	Exon 6 of 9	NP_001186068.1	Q9NPP4-1
	NLRC4	NM_021209.4		c.2357G>T	p.Gly786Val	missense	Exon 6 of 9	NP_067032.3	Q9NPP4-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NLRC4	ENST00000402280.6	TSL:1 MANE Select	c.2357G>T	p.Gly786Val	missense	Exon 6 of 9	ENSP00000385428.1	Q9NPP4-1
	NLRC4	ENST00000360906.9	TSL:1	c.2357G>T	p.Gly786Val	missense	Exon 6 of 9	ENSP00000354159.5	Q9NPP4-1
	NLRC4	ENST00000342905.10	TSL:1	c.362G>T	p.Gly121Val	missense	Exon 5 of 8	ENSP00000339666.6	Q9NPP4-2

Frequencies

GnomAD3 genomes AF: 0.00241 AC: 366 AN: 152094 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.000894

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00423

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00232 AC: 570 AN: 245338 AF XY: 0.00248

Gnomad AFR exome AF: 0.000818

Gnomad AMR exome AF: 0.00214

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000419

Gnomad NFE exome AF: 0.00399

Gnomad OTH exome AF: 0.00269

GnomAD4 exome AF: 0.00392 AC: 5713 AN: 1456228 Hom.: 16 Cov.: 31 AF XY: 0.00384 AC XY: 2781 AN XY: 724400

African (AFR) AF: 0.000604 AC: 20 AN: 33126

American (AMR) AF: 0.00225 AC: 98 AN: 43542

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26034

East Asian (EAS) AF: 0.00 AC: 0 AN: 39324

South Asian (SAS) AF: 0.000718 AC: 61 AN: 84998

European-Finnish (FIN) AF: 0.000657 AC: 35 AN: 53302

Middle Eastern (MID) AF: 0.000522 AC: 3 AN: 5752

European-Non Finnish (NFE) AF: 0.00478 AC: 5310 AN: 1109960

Other (OTH) AF: 0.00304 AC: 183 AN: 60190

GnomAD4 genome AF: 0.00240 AC: 366 AN: 152212 Hom.: 4 Cov.: 33 AF XY: 0.00210 AC XY: 156 AN XY: 74400

African (AFR) AF: 0.000891 AC: 37 AN: 41514

American (AMR) AF: 0.00190 AC: 29 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4826

European-Finnish (FIN) AF: 0.000189 AC: 2 AN: 10592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00423 AC: 288 AN: 68032

Other (OTH) AF: 0.00284 AC: 6 AN: 2110

Alfa AF: 0.00369 Hom.: 3

Bravo AF: 0.00255

TwinsUK AF: 0.00485 AC: 18

ALSPAC AF: 0.00389 AC: 15

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00453 AC: 39

ExAC AF: 0.00239 AC: 290

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	2	1	Periodic fever-infantile enterocolitis-autoinflammatory syndrome;C4015276:Familial cold autoinflammatory syndrome 4 (3)
-	-	1	Autoinflammatory syndrome (1)
-	-	1	NLRC4-related disorder (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	19
DANN	Benign	0.96
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.087	N
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.021	T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	1.9	L
PhyloP100		1.0
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.22
Sift	Benign	0.23	T
Polyphen		0.99	D
Vest4		0.53
MVP		0.52
MPC		0.65
ClinPred		0.023	T
GERP RS		2.8
Varity_R		0.058
gMVP		0.47

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs149451729; hg19: chr2-32463365;